Report of Pancreatic Atrophy in Two Patients Receiving Long-Term Sorafenib
In a letter to The New England Journal of Medicine, Ségolène Hescot, MD, of Université Paris Descartes, and colleagues reported evidence of irreversible pancreatic atrophy in two patients after long-term sorafenib treatment. Both patients received cumulative doses of sorafenib greater than 1,000 g over more than 2 years of treatment.
Loss of Pancreas Volume
The first patient received sorafenib for 2.5 years and exhibited a complete tumor response for 1 year. Sorafenib was initially given at 800 mg/d. Routine monitoring of plasma sorafenib concentrations showed that the median area under the curve (AUC) of sorafenib was 42 mg/L/h (range, 21–78 mg/L/h). After 3 months of sorafenib treatment, the patient developed intermittent grade 2 diarrhea, which resolved when treatment was interrupted and recurred when treatment was reinitiated.
Pancreatic exocrine insufficiency was diagnosed at 18 months after the start of sorafenib. The level of steatorrhea was 7.5 g per 24 hours (upper level of normal range, 4.5 g per 24 hours) and the fecal elastase level was twice the upper level of normal range. Control of diarrhea was improved with replacement of pancreatic enzymes. Volumetric computed tomography (CT) of the abdomen showed a 20% reduction in pancreas volume.
The second patient received sorafenib for 3 years at a median AUC of 31 mg/L/h (range, 22–80 mg/L/h); 2 months after starting treatment, the patient developed grade 1 diarrhea that was reversible with pancreatic-enzyme replacement. A 35% decrease in pancreas volume (from 37 mL to 24 mL) was detected by volumetric CT at 37 months after sorafenib initiation.
Reduced Microvasculature in Normal Tissue?
Acute diarrhea is a common early side effect of sorafenib. The authors noted that they have previously observed that pancreatic exocrine insufficiency could contribute to diarrhea in sorafenib-treated patients and that elevation of lipase levels have also been reported in patients receiving sorafenib.
They stated that, while much remains to be learned regarding the late side effects associated with long-term exposure to sorafenib, “We found that pancreatic atrophy might be a consequence of prolonged treatment…. The antiangiogenic properties of antivascular endothelial growth factor agents may reduce the microvasculature in normal tissues. This might account for the previously reported 8% loss in skeletal muscle in patients who have received sorafenib at 12 months (P < .01), the previously reported thyroid atrophy, and the pancreatic atrophy reported here.”
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